Guanethidine inhibits the function of postganglionic adrenergic neurons, thus inhibiting sympathetic function.

 Guanethidine uses the norepinephrine (N.E.) re-uptake transporter to reach its site of action, the neurosecretory vesicles.

• Guanethidine replaces norepinphrine in the vesicle and is released instead of the normal transmitter.

• Guanethidine is an inactive transmitter and the replacement of N.E. by an inactive agent is responsible for its antihypertensive effects (maintenance dosing).

 Adrenergic blockade by guanethidine results in post-synaptic supersensitivity.

 Sympathetic blockade by guanethidine produces venodilatation, reduction in cardiac output due to inhibition of cardiac sympathetic innervation, and blocks sympathetic reflex arteriolar response to the reduction in cardiac output.

Adverse Effects:

• Symptomatic hypotension (due to sympathetic reflex blockade)

• Sexual dysfunction (delayed ejaculation)

• Diarrhea

• Guanethidine effects blocked by N.E. reuptake blockers (tricyclic antidepressants, cocaine, ephedrine, amphetamine, chlorpromazine)